Project Summary Age-related defects in maintaining proteostasis are thought to be major contributing factors to a variety of degenerative diseases, including Alzheimer's and Parkinson's, as well as aging itself. A major contributing factor to these pathologies is the inability of the proteasome to keep up with the accumulation of mis-folded proteins, which eventually accumulate to levels sufficient to form cytotoxic amyloids. One therapeutic strategy to combat this process is to develop agonists of the proteasome-mediated turnover of mis-folded proteins, but progress has been frustratingly slow and no bona fide small molecule agonists are currently available. This R21 proposal asks for support to apply both novel chemistry and an innovative screening assay to solve this problem. If successful, this project will set the stage for a chemical biology-based exploration of the utility of proteasome stimulation in combating a variety of protein folding diseases for which good treatment options are not currently available.